Tumor infiltrating lymphocytes express multiple immune checkpoints and co-stimulatory receptors. Xencor’s bispecific tumor microenvironment (TME) activators seek to more effectively reactivate these tumor-killing T cells by engaging multiple T-cell targets simultaneously. This approach eliminates the need for the multiple antibodies and allows for more selective targeting of T cells with high checkpoint expression, which may potentially improve the therapeutic index of combination immunotherapies.
XmAb104 (previously XmAb23104) is an investigational XmAb bispecific antibody designed to promote tumor-selective T-cell activation by simultaneously targeting the immune checkpoint receptor, PD-1, and the immune co-stimulatory receptor, ICOS. Xencor’s XmAb® Bispecific Fc Domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb104. XmAb bispecific Fc domains have been engineered to eliminate Fc gamma receptor (FcγR) binding, with the intent to prevent activation and/or depletion of T cells via engagement by FcγR-expressing cells. In preclinical studies, synergistic PD-1 blockade and ICOS co-stimulation with XmAb104 significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo.
In the dose-escalation portion of an ongoing Phase 1 clinical study, XmAb104 has been well tolerated and is exhibiting a distinct safety profile compared to other clinical ICOS programs. The expansion portion of the study is testing XmAb104, with or without the anti-CTLA-4 antibody ipilimumab, as CTLA-4 blockade has been found to increase the frequency of ICOS-expressing T cells in multiple solid tumor types.
Each of Xencor’s bispecific TME activators tests a distinct mechanism of TME activation. Vudalimab (PD-1 x CTLA-4) is being evaluated in Phase 2 clinical studies.